INTRODUCTION: The host immune response and low vector efficiency have prevented effective cystic fibrosis (CF), a common, fatal, genetic disease. Pulmonary surrogate markers of CF disease require large patient numbers or long study durations. An alternative to pulmonary testing of CF gene transfer vectors is use of the maxillary sinuses as a surrogate model of CF lung disease. An adeno-associated virus vector (AAV-CFTR) was used in a phase I dose-escalation study followed by a phase II clinical trial to transfer CFTR cDNA into respiratory epithelial cells of the maxillary sinus of CF patients. This is the first CF gene therapy phase II study measuring clinical endpoints of CFTR gene transfer. METHODS: A randomized, unblinded, dose-escalation, within-subjects, phase I clinical trial of AAV-CFTR was conducted in the maxillary sinus of 10 CF patients with antrostomies. A randomized, double-blind, placebo controlled, within-subjects phase II clinical trial is in progress with 16 of 22 patients enrolled. The phase II study is powered to detect a 50% decrease in sinusitis recurrence using 22 patients with two-sided alpha 0.05 and beta 0.20. RESULTS: In the phase I study, the highest level of gene transfer was observed in the range of 0.1-1 AAV-CFTR vector copy per cell in biopsies obtained two weeks after treatment. Persistence was observed for up to 10 weeks. Dose-dependent changes in sinus transepithelial potential difference (TEPD) responses to pharmacological intervention were observed in 5 of 6 tested patients. Expression, measured by RT-PCR, was observed in 2 of 2 tested patients. Other phase II results are pending completion of study and breaking of blind. Both studies demonstrated little or no inflammatory or immune responses. CONCLUSION: AAV-CFTR administration to the maxillary sinus results in successful, dose-dependent gene transfer to the maxillary sinus and alterations in sinus TEPD suggestive of a functional effect, with little or no cytopathic or host immune response. Further study is warranted for AAV vectors as they may prove useful for CFTR gene transfer and other in vivo gene transfer therapies.